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PMID: 15657435 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stress-protecting genes.

Molecular and cellular biology ·Vol. 25 ·No. 3 ·2005-02-00 ·Pages 1089-99

Karapetian RN, Evstafieva AG, Abaeva IS, Chichkova NV, Filonov GS, Rubtsov YP, Sukhacheva EA, Melnikov SV, Schneider U, Wanker EE, Vartapetian AB

Abstract

Animal cells counteract oxidative stress and electrophilic attack through coordinated expression of a set of detoxifying and antioxidant enzyme genes mediated by transcription factor Nrf2. In unstressed cells, Nrf2 appears to be sequestered in the cytoplasm via association with an inhibitor protein, Keap1. Here, by using the yeast two-hybrid screen, human Keap1 has been identified as a partner of the nuclear protein prothymosin alpha. The in vivo and in vitro data indicated that the prothymosin alpha-Keap1 interaction is direct, highly specific, and functionally relevant. Furthermore, we showed that Keap1 is a nuclear-cytoplasmic shuttling protein equipped with a nuclear export signal that is important for its inhibitory action. Prothymosin alpha was able to liberate Nrf2 from the Nrf2-Keap1 inhibitory complex in vitro through competition with Nrf2 for binding to the same domain of Keap1. In vivo, the level of Nrf2-dependent transcription was correlated with the intracellular level of prothymosin alpha by using prothymosin alpha overproduction and mRNA interference approaches. Our data attribute to prothymosin alpha the role of intranuclear dissociator of the Nrf2-Keap1 complex, thus revealing a novel function for prothymosin alpha and adding a new dimension to the molecular mechanisms underlying expression of oxidative stress-protecting genes.

MeSH Terms
Active Transport, Cell Nucleus/genetics,physiology DNA-Binding Proteins/metabolism Gene Expression Regulation, Neoplastic/genetics,physiology HeLa Cells Humans Intracellular Signaling Peptides and Proteins Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 Oxidative Stress/genetics,physiology Protein Binding Protein Precursors/metabolism Proteins/metabolism RNA, Small Interfering/metabolism Thymosin/analogs & derivatives,metabolism Trans-Activators/metabolism Transcriptional Activation/genetics,physiology Tumor Cells, Cultured Two-Hybrid System Techniques
Chemicals
DNA-Binding Proteins Intracellular Signaling Peptides and Proteins KEAP1 protein, human Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 NFE2L2 protein, human Protein Precursors Proteins RNA, Small Interfering Trans-Activators prothymosin alpha Thymosin
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Karapetian Ruben N
Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia.
Evstafieva Alexandra G
Abaeva Irina S
Chichkova Nina V
Filonov Grigoriy S
Rubtsov Yuri P
Sukhacheva Elena A
Melnikov Sergey V
Schneider Ulrich
Wanker Erich E
Vartapetian Andrey B
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.3.1089-1099.2005
Published
2005-02-00
Pages
1089-99
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC544000
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.25.3.1089-1099.2005 PMC Full Text View journal details
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